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1.  Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial 
The lancet oncology  2013;14(4):371-382.
Summary
Background
Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry.
Methods
We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015.
Findings
Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21–43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24–47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28–51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3–4. The most common grade 3–4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%).
Interpretation
The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination.
Funding
National Cancer Institute and Cycle for Survival Fund, Memorial Sloan-Kettering Cancer Center.
doi:10.1016/S1470-2045(13)70049-4
PMCID: PMC3766955  PMID: 23477833
2.  Imatinib Mesylate in Advanced Dermatofibrosarcoma Protuberans: Pooled Analysis of Two Phase II Clinical Trials 
Journal of Clinical Oncology  2010;28(10):1772-1779.
Purpose
Dermatofibrosarcoma protuberans (DFSP) is a dermal sarcoma typically carrying a translocation between chromosomes 17 and 22 that generates functional platelet-derived growth factor B (PDGFB).
Patients and Methods
Two distinct phase II trials of imatinib (400 to 800 mg daily) in patients with locally advanced or metastatic DFSP were conducted and closed prematurely, one in Europe (European Organisation for Research and Treatment of Cancer [EORTC]) with 14-week progression-free rate as the primary end point and the other in North America (Southwest Oncology Group [SWOG]) with confirmed objective response rate as the primary end point. In the EORTC trial, confirmation of PDGFB rearrangement was required, and surgery was undertaken after 14 weeks if feasible. The SWOG study confirmed t(17;22) after enrollment.
Results
Sixteen and eight patients were enrolled onto the EORTC and SWOG trials, respectively. Tumor size ranged from 1.2 to 49 cm. DFSP was located on head/neck, trunk, and limb in seven, 11, and six patients, respectively, and was classic, pigmented, and fibrosarcomatous DFSP in 13, one, and nine patients, respectively. Metastases were present in seven patients (lung involvement was present six patients). Eleven patients (4%) had partial response as best response, and four patients had progressive disease as best response. Median time to progression (TTP) was 1.7 years. Imatinib was stopped in 11 patients because of progression, one patient because of toxicity, and two patients after complete resection of disease. Median overall survival (OS) time has not been reached; 1-year OS rate was 87.5%.
Conclusion
Imatinib is active in DFSP harboring t(17;22) including fibrosarcomatous DFSP, with objective response rate approaching 50%. Response rates and TTP did not differ between patients taking 400 mg daily versus 400 mg twice a day.
doi:10.1200/JCO.2009.25.7899
PMCID: PMC3040044  PMID: 20194851
3.  Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing’s sarcoma: a phase 1 expansion cohort study 
The lancet oncology  2009;11(2):129-135.
Summary
Background
Figitumumab is a fully human IgG2 monoclonal antibody targeting the insulin-like growth-factor-1 receptor (IGF-1R). Preclinical data suggest a dependence on insulin-like growth-factor signalling for sarcoma subtypes, including Ewing’s sarcoma, and early reports show antitumour activity of IGF-1R-targeting drugs in these diseases.
Methods
Between January, 2006, and August, 2008, patients with refractory, advanced sarcomas received figitumumab (20 mg/kg) in two single-stage expansion cohorts within a solid-tumour phase 1 trial. The first cohort (n=15) included patients with multiple sarcoma subtypes, age 18 years or older, and the second cohort (n=14) consisted of patients with refractory Ewing’s sarcoma, age 9 years or older. The primary endpoint was to assess the safety and tolerability of figitumumab. Secondary endpoints included pharmacokinetic profiling and preliminary antitumour activity (best response by Response Evaluation Criteria in Solid Tumours [RECIST]) in evaluable patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov, number NCT00474760.
Findings
29 patients, 16 of whom had Ewing’s sarcoma, were enrolled and received a total of 177 cycles of treatment (median 2, mean 6·1, range 1–24). Grade 3 deep venous thrombosis, grade 3 back pain, and grade 3 vomiting were each noted once in individual patients; one patient had grade 3 increases in aspartate aminotransferase and gammaglutamyltransferase concentrations. This patient also had grade 4 increases in alanine aminotransferase concentrations. The only other grade 4 adverse event was raised concentrations of uric acid, noted in one patient. Pharmacokinetics were comparable between patients with sarcoma and those with other solid tumours. 28 patients were assessed for response; two patients, both with Ewing’s sarcoma, had objective responses (one complete response and one partial response) and eight patients had disease stabilisation (six with Ewing’s sarcoma, one with synovial sarcoma, and one with fibrosarcoma) lasting 4 months or longer.
Interpretation
Figitumumab is well tolerated and has antitumour activity in Ewing’s sarcoma, warranting further investigation in this disease.
Funding
Pfizer Global Research and Development.
doi:10.1016/S1470-2045(09)70354-7
PMCID: PMC2941877  PMID: 20036194
4.  [F-18]-fluorodeoxy-D-glucose Positron Emission Tomography Response is Associated with Outcome for Extremity Osteosarcoma in Children and Young Adults 
Cancer  2009;115(15):3519-3525.
Background
Response to neoadjuvant chemotherapy is one of the most powerful prognostic factors for extremity osteosarcoma (OS). [F-18]-fluorodeoxy-D-glucose (FDG) positron emission tomography (PET) is a non-invasive imaging modality to predict histopathologic response. To determine the prognostic value of FDG PET response for progression-free survival (PFS) in OS, we reviewed the University of Washington Medical Center experience.
Methods
Forty patients with extremity OS were evaluated by FDG PET. All patients received neoadjuvant and adjuvant chemotherapy. FDG PET standard uptake values before (SUV1) and after (SUV2) neoadjuvant chemotherapy were analyzed and correlated with histopathologic response.
Results
The median SUV1, SUV2, and ratio of SUV2 to SUV1 (SUV2:1) were 6.8 (range 3.0−24.1), 2.3 (1.2−12.8), and 0.36 (0.12−1.10), respectively. Good FDG PET response was defined as SUV2 < 2.5 or SUV2:1 ≤ 0.5. FDG PET response by SUV2 or SUV2:1 were concordant with histologic response in 58% and 68% of patients, respectively. SUV2 was associated with outcome (four-year PFS 73% for SUV2 < 2.5 versus 39% for SUV2 ≥ 2.5, p=0.021. Initial disease stage and histologic response were both associated with outcome.
Conclusion
FDG PET imaging of extremity OS correlated only partially with histologic response to neoadjuvant chemotherapy. SUV2 < 2.5 was associated with improved PFS. Future prospective studies to determine whether FDG PET imaging is a predictor of outcome independent of initial disease stage are warranted.
doi:10.1002/cncr.24421
PMCID: PMC2716419  PMID: 19517457
osteosarcoma; fluorodeoxyglucose positron emission tomography; outcome
5.  The epidemiology of malignant giant cell tumors of bone: an analysis of data from the Surveillance, Epidemiology and End Results Program (1975–2004) 
Rare Tumors  2009;1(2):e52.
Malignant giant cell tumor (GCT) of bone is a rare tumor with debilitating consequences. Patients with GCT of bone typically present with mechanical difficulty and pain as a result of bone destruction and are at an increased risk for fracture. Because of its unusual occurrence, little is known about the epidemiology of malignant GCT of bone. This report offers the first reliable population-based estimates of incidence, patient demographics, treatment course and survival for malignancy in GCT of bone in the United States. Using data from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program, we estimated the overall incidence and determinants of survival among patients diagnosed with malignant GCT of bone from 1975–2004. Cox proportional hazards regression was used to evaluate demographic and clinical determinants of survival among malignant GCT cases. Based on analyses of 117 malignant GCT cases, the estimated annual incidence in the United States was 1.6 per 10,000,000 persons per year. Incidence was highest among adults aged 20 to 44 years (2.4 per 10,000,000 per year) and most patients were diagnosed with localized (31.6%) or regional (29.9%) disease compared to distant disease (16.2%). Approximately 85% of patients survived at least 5 years, with survival poorest among older patients and those with evidence of distant metastases at time of diagnosis. The current study represents the largest systematic investigation examining the occurrence and distribution of malignancy in GCT of bone in the general U.S. population. We confirm its rare occurrence and suggest that age and stage at diagnosis are strongly associated with long-term survival.
doi:10.4081/rt.2009.e52
PMCID: PMC2994468  PMID: 21139931
giant cell tumor of bone; surveillance; epidemiology and end results; descriptive epidemiology; incidence; survival; osteosarcoma.
6.  Identification of Recurrent NAB2-STAT6 Gene Fusions in Solitary Fibrous Tumor by Integrative Sequencing 
Nature genetics  2013;45(2):180-185.
A 44-year old woman with recurrent solitary fibrous tumor (SFT)/hemangiopericytoma was enrolled in a clinical sequencing program including whole exome and transcriptome sequencing. A gene fusion of the transcriptional repressor NAB2 with the transcriptional activator STAT6 was detected. Transcriptome sequencing of 27 additional SFTs all revealed the presence of a NAB2-STAT6 gene fusion. Using RT-PCR and sequencing, we detected this fusion in 51 of 51 SFTs, indicating high levels of recurrence. Expression of NAB2-STAT6 fusion proteins was confirmed in SFT, and the predicted fusion products harbor the early growth response (EGR)-binding domain of NAB2 fused to the activation domain of STAT6. Overexpression of the NAB2-STAT6 gene fusion induced proliferation in cultured cells and activated EGR-responsive genes. These studies establish NAB2-STAT6 as the defining driver mutation of SFT and provide an example of how neoplasia can be initiated by converting a transcriptional repressor of mitogenic pathways into a transcriptional activator.
doi:10.1038/ng.2509
PMCID: PMC3654808  PMID: 23313952
7.  R1507, a Monoclonal Antibody to the Insulin-Like Growth Factor 1 Receptor, in Patients With Recurrent or Refractory Ewing Sarcoma Family of Tumors: Results of a Phase II Sarcoma Alliance for Research Through Collaboration Study 
Journal of Clinical Oncology  2011;29(34):4541-4547.
Purpose
The type 1 insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the pathogenesis of the Ewing sarcoma family of tumors (ESFT). We conducted a multicenter phase II study of the fully human IGF-1R monoclonal antibody R1507 in patients with recurrent or refractory ESFT.
Patients and Methods
Patients ≥ 2 years of age with refractory or recurrent ESFT received R1507 at doses of 9 mg/kg intravenously one a week or 27 mg/kg intravenously every three weeks. Response was measured by using WHO criteria. Tumor imaging was performed every 6 weeks for 24 weeks and then every 12 weeks.
Results
From December 2007 through April 2010, 115 eligible patients from 31 different institutions were enrolled. The median age was 25 years (range, 8 to 78 years). The location of the primary tumor was bone in 57% of patients and extraskeletal in 43% of patients. A total of 109 patients were treated with R1507 9 mg/kg/wk, and six patients were treated with 27 mg/kg/3 wk. The overall complete response/partial response rate was 10% (95% CI, 4.9% to 16.5%). The median duration of response was 29 weeks (range, 12 to 94 weeks), and the median overall survival was 7.6 months (95% CI, 6 to 9.7 months). Ten of 11 responses were observed in patients who presented with primary bone tumors (P = .016). The most common adverse events of grades 3 to 4 were pain (15%), anemia (8%), thrombocytopenia (7%), and asthenia (5%).
Conclusion
R1507 was a well-tolerated agent that had meaningful and durable benefit in a subgroup of patients with ESFT. The identification of markers that are predictive of a benefit is necessary to fully capitalize on this approach.
doi:10.1200/JCO.2010.34.0000
PMCID: PMC3236654  PMID: 22025149

Results 1-7 (7)